This proposal outlines the development of a strong, interactive research program in breast cancer at Case Western Reserve University and its affiliate hospitals University Hospitals of Cleveland and Metrohealth Medical Center. The principle objective will be to catalyze a breast cancer program development based on a synergistic, interdisciplinary integration of the scientific, clinical and organizational expertise of physicians and scientists from the Departments of Surgery, Medicine, Epidemiology and Biostatistics, Radiology, Pathology, Pharmacology, Molecular Biology, Genetics and Biochemistry at CWRU. The central scientific goals will be the development of molecular markers and therapy for breast cancers, and understanding the signals for oncogenesis and cell death in breast cancer cells. Five pilot projects are described: Each focuses on a specific theme which forms the basis for interactions and development with other investigators. The project leaders are to coordinate these collaborative efforts and the development of the program. Project 1 will identify novel tyrosine kinases and their oncogenic signals in human breast cancers, with eventual goal to develop molecular markers for breast cancers. Project 2 will study the mechanism of programmed cell death of breast cancers with potential to develop therapeutic agents. Project 3 will develop immunotherapy strategies for breast cancers by gene and protein delivery. Project 4 will test the hypothesis that chemical carcinogenesis potentiates the mammary tumorigenesis of different oncogenes such as H-ras, c-myc and neu. Project 5 will implement Phase II clinical trials based on novel strategies which target DNA metabolizing enzymes. Three core facilities will be developed to foster interdisciplinary translational research among members of the breast cancer program. A tissue procurement and breast cancer cell model core will provide CWRU investigators with access to clinical specimens and human breast cancer models. A key advantage of this core will be to insure that collaborating investigators are using the same reagents. A clinical trials core and a biostatistics/ epidemiology core will support the clinical initiatives and facilitate development of translational research projects. The long term goal of this developmental program is to establish a critical number of NIH funded investigators with a common interest in understanding the pathogenesis of breast cancer and the development of more effective markers and therapy for women with breast cancer.